This is a new project in which we will use the tools and information generated by the Human Genome Project to identify new genes that determine plasma levels of lipoproteins and susceptibility to atherosclerosis. This project combines all of the human genetics studies of the ongoing Program Project into a single effort. Over the last two years, we have prepared for this change by establishing the infrastructure to map genes and identify DNA sequence variations using high through-put methodologies, including genome scanning, automated DNA sequencing, variant detector arrays, and heteroduplex chromatography. By concentrating all of our human genetic studies into a single project, we will enhance our ability to discover new genes and sequence variations that determine the levels and distributions of plasma lipids in humans. Two general approaches will be taken in this project. First, we will perform linkage studies in dyslipidemic families to map and identify new genes involved in cholesterol homeostasis. The identification of genes contributing to the most common forms of hyperlipidemia has been complicated by the fact that multiple factors, both genetic and environmental, influence plasma lipoprotein levels. To circumvent this problem, we will focus our efforts on large, phenotypically well-defined families in which the segregation of dyslipidemia suggests the effect of a single major gene. Second, we will analyze the frequency of single nucleotide polymorphisms (SNPs) in wellcharacterized hyperlipidemic and normolipidemic individuals to identify sequence variations that 1) contribute to inter-individual differences in plasma lipoprotein levels in the population, and 2) confer susceptibility or resistance to accelerated coronary atherosclerosis, the most devastating consequence of dyslipidemia.